Montelukast sodium is used in the treatment of asthma. It is commercialized under the name of SINGULAIR™ (Merck) as oral tablets, chewable tablets and granules. Montelukast sodium has the following structure:

Montelukast is a leukotriene receptor antagonist and an inhibitor of leukotriene biosynthesis. U.S. Pat. No. 5,565,473 discloses and claims the compound and the methods for use. Montelukast is synthesized in a number of ways. The synthesis described in the patent involved methyl esters such as methyl 2-[(3S)-[3-[(2E)-(7-chloroquinolyn-2-yl)ethenylphenyl]-3-hydroxipropyl]benzoate and comprised the coupling between methyl 1-(mercaptomethyl)-cyclopropaneacetate and an appropriate mesilate produced in situ. The methyl ester of Montelukast was hydrolyzed into its acid form and directly transformed into its corresponding sodium salt. The tedious chromatographic purifications of the methyl esters and final products required make the above process unsuitable for large scale production. Additionally, the yields obtained are poor.
EP 737.186 B1 discloses an improved process for the synthesis of Montelukast sodium and dicyclohexylammonium Montelukast, which differed from the process described in EP 480.717 B1 in the use of the dilithium salt of 1-(mercaptomethyl)cyclopropaneacetic acid, instead of the methyl ester for the coupling reaction with the mesylate. The mesylate had the same formula as in EP 480.717 B1 but was added in its crystalline form. The process directly yields Montelukast in its acid form, which is further transformed into its dicyclohexylamine salt, which crystallizes in two different polymorphs. From the purified and crystalline dicyclohexylamine salt, Montelukast in its acid form was recovered by treatment with acid, and then the sodium salt was obtained by treatment of the free acid with a source sodium ions.
Commercially produced Montelukast (the -trans enantiomer) typically include a number of impurities. Examples of the major impurities have the following structures:
Montelukast Cis-Enantiomer
Montelukast Sulfoxide
Montelukast Dehydro
U.S. Pat. No. 5,565,473 to BELLEY et al. (see also corresponding EP 0 480 717) discloses a genus of pharmaceutically useful compounds that encompasses Montelukast and salts thereof. Example 161 of BELLEY et al. purports to make the sodium salt of Montelukast via the free acid.
Similarly, WO 95/18107 discloses methods of preparing, inter alia, Montelukast and it salts. Montelukast is converted in situ to the readily isolatable crystalline dicyclohexylamine salt and then subsequently converted to the sodium salt. According to WO 95/18107 this offers a simple and efficient method for the purification of Montelukast and for the preparation of the crystalline Montelukast sodium.
A similar disclosure is found in U.S. Pat. No. 5,523,477 to KING et al. Example 2 shows the formation of Montelukast and conversion into the dicyclohexylamine salt, which is then precipitated. Example 3 shows the conversion of the Montelukast dicyclohexylamine salt to Montelukast sodium by dissolving the solid dicyclohexylamine salt in toluene and adding acetic acid to reform the free acid. Then sodium hydroxide is added to the organic layer containing the acid (Montelukast).
Commercial production of pharmaceutical grade Montelukast sodium typically requires the acidification of the crude Montelukast mixture. The Montelukast is in a free acid form after the final synthesis step. This free acid form is then reacted with a cyclo-aliphatic amine having a basic character. This acid-base reaction is very specific, neutralizing only the Montelukast-trans form. The resulting solution is crystallized to isolate the Montelukast-trans salt in solution. The Montelukast sodium is obtained by the addition of sodium hydroxide in molar excess to the recovered Montelukast-trans salt in solution to replace the cyclo-alaphatic amine group.
A paper entitled, “Effect of light and heat on the stability of Montelukast in solution and in its solid state,” by Mahmoud Al Omani, et al., Journal of Pharmaceutical and Biomedical Analysis, 45, 465-471, 2007, discloses an number of methods for using a selective HPLC system to measure Montelukast and its major impurities including Montelukast-cis, Montelukast-cis, the Montelukast sulfoxide and the Montelukast dehydro impurities. Montelukast in solution was shown to be unstable when exposed to light leading to the formation of the Montelukast-cis isomer, and disclosed to degrade rapidly in acidic solutions. The disclosed analytical method employed glacial acetic acid and methanol as a mobile phase and octadecyl silane as the stationary phase. A chromatogram produced by this system showed a good separation between Montelukast and the related impurities.
The USP grade acceptance criteria of Montelukast sodium is shown in the following table:
Component:Percent (by weight)Montelukast-trans**Montelukast-Sulfoxide0.1Montelukast-cis0.1Michael Adducts0.1Ketonic0.1Montelukast-Styrenic Impurities0.3** Acceptance criteria: 98.0%-102.0 wt-%, on the anhydrous basis by HPLC
Over forty years ago, a new process was developed specifically for large scale industrial purifications. U.S. Pat. No. 2,985,589 disclosed a chromatography system involving a separation tower divided into a number of individual separation beds. These beds are connected in series, and the outlet at the bottom most bed is connected to a pump that retuned flow in a continuous loop to the upper most bed. The inlet apparatus for each bed has a port connected to a downward flowing conduit. The conduits terminate in fittings attached to a rotary valve designed to control both ingress and egress of liquids into or from the inlets to each individual bed. The system is called Simulated Moving Bed (SMB) chromatography because the beds appear to be moving in a direction countercurrent to the direction of flow. There are hundreds, if not thousands of adsorbents which have been used for simulated moving bed systems, some of which include resins, zeolites, alumina, and silica.
Simulated Moving Bed (SMB) technology represents a variation on the principles of high performance liquid chromatography. SMB can be used to separate particles and/or chemical compounds that would be difficult or impossible to separate by any other means. Furthermore, SMB technology represents a continuous process which provides a significant economic and efficiency advantages in manufacturing operations compared to batch typical batch separation methods including crystallization and stepwise chromatographic separations.
The continuous nature of SMB operation is characterized by very brief flow stoppages during the port switchovers in successive process steps. However, since all input and output conduits briefly stop at the same time, there are no significant pressure drops or surges in the system. Indexing of mechanical rotors is designed to effect rapid switchovers, even on very large industrial machines. Further, strategy in the design of process configuration is largely dictated by the affinity and release characteristics of bound species to the solid substrate, exclusion properties of unbound species, the bed volume required to obtain separation of by-product, and other factors.
There are more than 200 issued patents on modifications of SMB technology that disclose improvements in separation efficiency generally, or in particular applications, enhanced purity and yield in the final products, or reduction in required volume desorbent. For example, in one variation disclosed in U.S. Pat. No. 5,156,736, separations are performed in a single bed preserving the principles of SMB by interposing at various levels in the bed a series of crossectionally functional collecting and distribution means for adding feedstock and recycled process liquid, collecting raffinate, distributing eluent, and recovering extract product. Equilibrium is established in the system by very precise flow and pressure control.
It is the objective of the invention to replace the current chemical purification steps of acidification of the crude Montelukast, crystallization, isolation, and amine group replacement with a continuous purification process employing simulated moving bed technology.
It is a further object of the invention to reduce or eliminate loss of the key -trans form of Montelukast sodium to the -cis impurity form by carrying out the process in a closed continuous manner with fewer opportunities for exposure to light and acid to reduce the potential loss of the -trans form to the formation of impurities.
It is a still further object of the invention to reduce the Montelukast styrenic impurity by the elimination of an acidifying step in the purification.